Increasing evidence implicates myeloperoxidase (MPO) in oxidative damage leading to atherosclerosis. MPO is expressed in macrophages at atherosclerotic lesions, and generates hypochlorous acid (HOC1), a toxic chlorinating and oxidizing agent. Oxidation of low density lipoprotein (LDL) by MPO promotes its uptake by macrophages, leading to lipid-laded foam cells. High density lipoprotein (HDL) is protective against atherosclerosis, promoting the efflux of cholesterol from foam cell macrophages. Recent findings indicate that MPO selectively oxidizes the apoAl component of HDL in lesions, inhibiting ABCA1-mediated cholesterol efflux from macrophages. As further evidence linking MPO to risk, higher MPO levels in serum correlates with increased incidence of CVD events, As further evidence linking MPO to atherosclerosis risk, higher levels of MPO in serum and circulating cells have been correlated with increased incidence of cardiovascular disease (CVD) events. Moreover, a promoter polymorphism, -463G/A, which supports higher MPO gene expression, has been linked to increased frequency of CVD events, progression of atherosclerosis, and endothelial dysfunction). Mouse models are critically important for investigations of molecular pathways underlying multigenic disease states such as atherosclerosis. Current mouse models for atherosclerosis cannot be used to investigate MPO involvement because the mouse MPO gene is not expressed in macrophages at lesions. To remedy this, we generated transgenic mice expressing the human MPO G and A alleles, and showed the MPOG transgene is expressed at lesions in the LDL receptor knockout model (LDLR-/-). The proposed experiments will investigate the role of MPO-generated oxidants in atherosclerosis using the MPO transgenics crossed to the LDLR-/- model and the human apolipoprotein E4 knockin model. The specific hypothesis of this proposal is that MPO-generated oxidants influence cholesterol and lipid metabolism, and promote formation of atherosclerosis lesions. Aim 1 will test whether the MPOG transgene promotes more severe atherosclerosis in LDLR-/- mice. We will look for MPO-dependent changes in size or severity of aortic lesions, and changes in levels of serum cholesterol, HDL, and triglycerides. We will examine MPO-dependent oxidation of apoA-1, and assay effects on cholesterol efflux. Aim 2 will use the apoE4 knockin mice to determine if MPOG and apoE4 synergize to promote atherosclerosis. These studies will reveal if MPO-generated oxidants promote atherosclerosis in mouse models, thereby humanizing existing mouse models, and enabling investigations of the role of MPO-mediated oxidation in atherosclerosis.